Alzheimer's disease (AD) is the leading cause of dementia and the fourth leading cause of death affecting 4 million Americans. There is no known cure. Our long term goal is to develop a drug which will effectively slow, halt or reverse the progression of AD to death. An animal model is essential for the development of effective drugs and we propose to make a mouse model of the neurofibrillary tangle (NFT) pathology that is associated with neuronal degeneration in the brains of patients with AD. Neurofibrillary tangles are mainly composed of Tau protein in a hyperphosphorylated state. We hypothesize that mouse-Tau and human-Tau are not equivalent. This hypothesis is strongly supported by the observation that neurofibrillary tangles are observed in human brain neurons, particularly from patients with Alzheimer's, but have not been reported to be present in mouse brain. Specifically, we propose to remove the mouse Tau gene generating a Tau-knockout mouse which lacks Tau in this Phase I SBIR. In Phase II, we will add the human gene for Tau to these Tau-knockout mice generating "humanized-Tau mice" and measure human-Tau, human-phosho-Tau and human-NFTs before and after mating to our "humanized apoE mice". PROPOSED COMMERCIAL APPLICATION To provide an animal model of Alzheimer's disease pathology. This model has the potential to help elucidate the biochemical mechanisms causing neurodegeneratin in Alzheimer's disease. Such a model is not currently available and is required to develop effective anti-Alzheimer's treatments.